Interleukin-1 (IL-1) is a multifunctional cytokine which comprises a family of two polypeptides, IL-1.alpha. and IL-1.beta., with a wide spectrum of activities. IL-1.alpha. and IL-1 .beta. have been found to possess inflammatory, metabolic, physiologic, hematopoeitic and immunologic properties. Although both forms of IL-1 are distinct gene products, they recognize the same cell surface receptors (i.e. IL-1 receptors, IL-1RtI and IL-1RtII).
Besides skin keratinocytes, some epithelial cells and certain cells in the central nervous system, significant amounts of mRNA encoding IL-1 are not observed in most other healthy cells. However, IL-1 production is dramatically increased by a variety of cells in response to infection, microbial toxins, inflammatory agents, products of activated lymphocytes, complement and clotting components. In addition, IL-1 has been recognized as a prototype of proinflammatory cytokines in that it induces the expression of a variety of genes and the synthesis of several proteins that in turn, induce acute and chronic inflammation. Thus, circulating IL-1 has been implicated in various disease states including sepsis, rheumatoid arthritis, stroke and diabetes. Dinarello (1991) Blood 77(8):1627-1652.
In addition, IL-1 has been shown to regulate bone reabsorption and bone formation with its major activity in bone metabolism being osteoclast activation. See Gowen et al. (1983) Nature 306:378-380. In fact, IL-1 has been reported to be a potent stimulator of bone reabsorption and has also been reported to increase prostaglandin synthesis in bone. Lorenzo et al. (1987) Endocrinology 121:1164-1170.
A natural occurring inhibitor of IL-1 which specifically inhibits IL-1 activity has also been identified. Carter et al. (1990) Nature 344:633. This protein, called IL-1 receptor antagonist protein (IL-1ra), has been shown to compete with the binding of IL-1 to its surface receptors. Thus, significant interest has arisen in administering IL-1ra to block the activity of IL-1 in various diseases including septic shock (Ohlsson et al. (1990) Nature 348:550-556), immune complex-induced colitis (Cominelli (1990) J. Clin. Invest. 86:972-979), acute myelogenous leukemia (Rambaldi et al. (1990) Blood 76:114-120) and osteoporosis (Pacifici et al. (1993) J. Clin. Endocrinol. Metab. 77:1135-1141).